Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32488064, 33084218, 28792770, 25976102, 29655203, 19793312, 31440721, 23266810, 33377563, 31283065)
ClinVar Genomic variation as it relates to human health
NM_000391.4(TPP1):c.827A>T (p.Asp276Val)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000391.4(TPP1):c.827A>T (p.Asp276Val)
Variation ID: 207581 Accession: VCV000207581.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 6616720 (GRCh38) [ NCBI UCSC ] 11: 6637951 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 7, 2015 Oct 26, 2024 Jan 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000391.4:c.827A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000382.3:p.Asp276Val missense NC_000011.10:g.6616720T>A NC_000011.9:g.6637951T>A NG_008653.1:g.7742A>T LRG_830:g.7742A>T LRG_830t1:c.827A>T LRG_830p1:p.Asp276Val - Protein change
- D276V
- Other names
-
p.D276V:GAT>GTT
- Canonical SPDI
- NC_000011.10:6616719:T:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TPP1 | - | - |
GRCh38 GRCh37 |
1154 | 1185 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV000189773.11 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 20, 2023 | RCV000666770.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2022 | RCV002485283.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791120.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000243421.11
First in ClinVar: Aug 07, 2015 Last updated: May 20, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32488064, 33084218, 28792770, 25976102, 29655203, 19793312, 31440721, 23266810, 33377563, 31283065) (less)
|
|
|
Pathogenic
(Jan 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Accession: SCV001146849.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Indication for testing: Ceroid lipofuscinosis neuronal 2
Age: 10-19 years
Sex: male
Geographic origin: Argentina
|
|
|
Pathogenic
(Apr 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 2
Autosomal recessive spinocerebellar ataxia 7
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002779352.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022407.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000951555.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein (p.Asp276Val). This variant is present in population databases (rs763162812, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 22832778, 23266810, 25976102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 207581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005382371.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
The observed missense c.827A>T(p.Asp276Val) variant in TPP1 gene has been reported previously in multiple individuals affected with neuronal ceroid lipofuscinosis type 2 (Kohan R, et … (more)
The observed missense c.827A>T(p.Asp276Val) variant in TPP1 gene has been reported previously in multiple individuals affected with neuronal ceroid lipofuscinosis type 2 (Kohan R, et al., 2015; Kohan R, et al., 2013; Kohan R, et al., 2009). Experimental studies indicate that this variant impacts the catalytic machinery of TPP1 gene (Walus M, et al., 2005). The p.Asp276Val variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 276 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the nervous system (present)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 2
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455835.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein (p.Asp276Val). This variant is present in population databases (rs763162812, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 22832778, 23266810, 25976102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 207581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed missense c.827A>T(p.Asp276Val) variant in TPP1 gene has been reported previously in multiple individuals affected with neuronal ceroid lipofuscinosis type 2 (Kohan R, et al., 2015; Kohan R, et al., 2013; Kohan R, et al., 2009). Experimental studies indicate that this variant impacts the catalytic machinery of TPP1 gene (Walus M, et al., 2005). The p.Asp276Val variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 276 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32488064, 33084218, 28792770, 25976102, 29655203, 19793312, 31440721, 23266810, 33377563, 31283065)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein (p.Asp276Val). This variant is present in population databases (rs763162812, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 22832778, 23266810, 25976102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 207581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed missense c.827A>T(p.Asp276Val) variant in TPP1 gene has been reported previously in multiple individuals affected with neuronal ceroid lipofuscinosis type 2 (Kohan R, et al., 2015; Kohan R, et al., 2013; Kohan R, et al., 2009). Experimental studies indicate that this variant impacts the catalytic machinery of TPP1 gene (Walus M, et al., 2005). The p.Asp276Val variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 276 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina. | Kohan R | Biochimica et biophysica acta | 2015 | PMID: 25976102 |
| Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America. | Kohan R | Gene | 2013 | PMID: 23266810 |
| Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. | Pérez-Poyato MS | Journal of child neurology | 2013 | PMID: 22832778 |
| An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients. | Kohan R | Clinical genetics | 2009 | PMID: 19793312 |
Text-mined citations for rs763162812 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.